The racemic mixture of [[4-(1,4,5,6-tetrahydro-4-methyl-6-oxo-3-pyridazinyl)phenyl]hydrazono]prop anedinitrile (I) has been described earlier in the applicant's European Patent No. 38:3449 B1. It was shown that compound (I) is potent in the treatment of congestive heart failure and has significant calcium dependent binding to troponin. ##STR1##
Optically active enantiomers of (I) have been earlier described in the applicant's European Patent No. 565546 B1. It was shown that the cardiotonic potency is predominantly due to the (-) enantiomer of (I). A method for preparing pure (-) enantiomer of (I) using optically pure (-) enantiomer of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone (II) as an intermediate compound was also disclosed. ##STR2##
The racemic compound (II) can be synthesized by methods known in the literature (J. Med. Chem., 17, 273-281 (1974)). The resolution of the racemic compound (II) has, however, been proved very difficult because the 4-amino group in the molecule is weakly basic. The salts of 6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone with optically active acids hydrolyse on crystallization readily back to the compound (II) and to the resolving compound which interfere the resolution procedure or make it totally impossible.
The separation of the pure enantiomers of compound (II) on a chiral HPLC-column has been described in European patent application No. 208518. This method is, however, not applicable for industrial scale. An enantioselective seven step synthesis of (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone starting from (+)-2-chloropropionic acid has also been described in the literature (J. Org. Chem., 56, 1963 (1991)). The total yield in this method is only 12% giving (-)-6-(4-aminophenyl)-4,5-dihydro-5-methyl-3(2H)-pyridazinone with an optical purity of 97.2%.
In the above mentioned European Patent No. 565546 B1 it was found that the racemic intermediate (II) can be resolved by treating (II) with L- or D-tartaric acid in excess in 2-propanol and recovering the diastereomeric crystalline salt. Optical purity of the product was further increased by dissolving the recovered basified product in dioxane. The racemic residue was crystallized from dioxane and the filtrate was evaporated to dryness yielding the desired pure enantiomer of the intermediate (II). The pure (-) enantiomer of (I) was prepared by treating (-) enantiomer of the intermediate (II) further with sodium nitrite and malononitrile in acidic conditions as described in the above mentioned European Patent No. 383449 B1.
Even if this process gives pure (-) enantiomer of (I), the necessity to use harmful dioxane limits its applicability in the large scale. Therefore there is a need for an improved process for preparing pure (-) enantiomer of (I).